Human target validation of phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using AZD6482 a novel PI3Kβ inhibitor

Nylander S, Kull B, Bjorkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson M, Skarby T, Inghardt T, Fjellstrom O, Gustafsson D. Human target validation of phosphoinositide 3-kinase (PI3K)beta:effects on platelets and insulin sensitivity, using AZD6482 a novel PI3K beta inhibitor. J Thromb Haemost 2012; 10: 212736. See also Jackson SP, Schoenwaelder SM. Antithrombotic phosphoinositide 3-kinase beta inhibitors in humans a shear delight! This issue, pp 21236. Summary. Background: Based on in vitro and animal data, PI3K beta is given an important role in platelet adhesion and aggregation but its role in insulin signaling is unclear. Objective: To strengthen the PI3K beta target validation using the novel, short-acting inhibitor AZD6482. Methods and results: AZD6482 is a potent, selective and ATP competitive PI3K beta inhibitor (IC50 0.01 mu m). A maximal anti-platelet effect was achieved at 1 mu m in the in vitro and ex vivo tests both in dog and in man. In dog, in vivo AZD6482 produced a complete anti-thrombotic effect without an increased bleeding time or blood loss. AZD6482 was well tolerated in healthy volunteers during a 3-h infusion. The ex vivo anti-platelet effect and minimal bleeding time prolongation in the dog model translated well to data obtained in healthy volunteers. AZD6482 inhibited insulin-induced human adipocyte glucose uptake in vitro (IC50 of 4.4 mu m). In the euglycemic hyperinsulinemic clamp model, in rats, glucose infusion rate was not affected at 2.3 mu m but reduced by about 60% at a plasma exposure of 27 mu m. In man, the homeostasis model analysis (HOMA) index increased by about 1020% at the highest plasma concentration of 5.3 mu m. Conclusions: This is the first human target validation for PI3K beta inhibition as anti-platelet therapy showing a mild and generalized antiplatelet effect attenuating but not completely inhibiting multiple signaling pathways with an impressive separation towards primary hemostasis. AZD6482 at supratherapeutic plasma concentrations may attenuate insulin signaling, most likely through PI3Ka inhibition.